Search

Summary Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B‐cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein‐to‐vein time and infusion rate did not differ between bridging modalities. RT‐bridged patients had favourable outcomes with 1‐year progression‐free survival (PFS) of 56% for single modality and 47% for CMT (1‐year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high‐risk disease, with low dropout rates and excellent outcomes. [ABSTRACT FROM AUTHOR]

Summary: The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL. [ABSTRACT FROM AUTHOR]

Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic. [ABSTRACT FROM AUTHOR]

Summary: Large B‐cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi‐cel) or tisagenlecleucel (tisa‐cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa‐cel versus axi‐cel (52% vs. 48%) compared to 20% versus 80% in ASCT‐fit patients; p < 0.0001. The drop‐out rate from approval to infusion was significantly higher in the ASCT‐unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression‐free and overall survival were similar in both cohorts. CAR T was well‐tolerated in ASCT‐unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real‐world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant. [ABSTRACT FROM AUTHOR]

Background. A retrospective study of the clinical, epidemiologic, and virologic features of norovirus gastroenteritis in 12 adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. Methods. Norovirus infection was diagnosed by reverse-transcriptase polymerase chain reaction. Strains were genotyped by nucleic acid sequence of the most highly conserved region of the norovirus gene encoding the capsid S (shell) domain. Results. Ten of 12 patients presented with vomiting of short duration, but diarrhea was present in all. The median time from onset to norovirus diagnosis was 1 month (range, 0.25-6.0 months). Eleven patients were receiving immunosuppression when norovirus infection was diagnosed: 8 for graft-versus-host disease (GVHD) in an organ other than gut, 1 for previous gut GVHD, and 2 for presumed gut GVHD that proved to be norovirus gastroenteritis. Six patients required enteral or parenteral nutrition for severe weight loss. In 10 patients, diarrhea lasted a median of 3 months (range, 0.5-14 months) and virus was shed at a high level throughout. The remaining 2 patients died after 4 months of diarrhea (one died of unrelated complications, and the other died of malnutrition). The noroviruses found were GII (untyped), GII-3, GII-4, and GII-7 in 1, 1, 9, and 1 patients, respectively. Eleven of the 12 patients had acquired their infection in the community. Phylogenetic analysis of the GII-4 strains demonstrated that all differed. Conclusions. Noroviruses are a hitherto unsuspected cause of prolonged morbidity and mortality in adults after allogeneic HSCT. The use of reverse-transcriptase polymerase chain reaction to detect high viral load levels in feces distinguishes norovirus gastroenteritis from gut GVHD. [ABSTRACT FROM AUTHOR]

Background: Ultraviolet (UV) radiation damages the cellular DNA of skin cells. In response, wild-type p53 protein accumulates in irradiated cells and the stabilized and transactivated protein can then induce genes involved in cell cycle arrest in G1, or in the initiation of apoptosis. Selenium protects cells from UVB-induced cell death and apoptosis by mechanisms which are unclear, although recent reports suggest that selenium protects against UV-induced cell damage by inducing DNA repair enzymes and transactivating p53. Methods: We examined whether selenomethionine could protect human skin cells from UV radiation-induced p53 transactivation, using a pRGCΔ fos-lacZ p53-dependent reporter construct stably transfected in an amelanotic melanoma cell line (Arn-8) which expresses wild-type p53. Cells were pretreated with or without selenomethionine and then irradiated with broadband UVB (∼270–350 nm); 0–30 mJ/cm2 from a Phillips TL100 W/12 lamp. Results: The percentage of cells with transcriptionally active p53 increased dose dependently up to 20 mJ/cm2 UVB. Treatment with 50 μM selenomethionine for 24 h both pre- and post-irradiation, significantly diminished p53 activation by 30–43% across the UV dose range ( P=0.0085, n=5 independent experiments) and decreased UV-induced p53 protein accumulation as assessed by Western blotting. Conclusions: We conclude that selenomethionine inhibits broad band UVB-induced p53 transactivation and protein accumulation and that this effect correlates with reported protective effects of selenium against UV-induced DNA damage. [ABSTRACT FROM AUTHOR]

Laboratory-specific cut-off lupus ratios (LR), above which a plasma is judged positive for lupus anticoagulant (LA), were established for both activated partial thromboplastin time-based and dilute Russell viper venom time-based methods. The validity of using these cut-off values to determine the presence of LA in patients on oral anticoagulation (OAC) was assessed. A cohort of 40 patients (23 male and 17 female), aged 22–84 years (mean 52 years) were tested for LA at the time of a thrombotic event. Repeated testing was performed after the same patients were treated with OAC (international normalized ratio 2.0–3.5). For 36 patients (90%), LA status was unchanged pre- and on-OAC. Thirteen of the 40 patients (32.5%) were positive for LA both pre- and on-OAC. Of the 27 patients negative for LA pre-OAC, 23 remained negative on-OAC. The four discordant results were interesting in that LA positivity was demonstrated only after the patient was stable on-OAC. In our cohort of 40 patients, there was a trend for LRs to decrease on-OAC, but this did not reach statistical significance. The subset (4) went against this trend and became positive after the thrombotic event. [ABSTRACT FROM AUTHOR]

Leukemia inhibitory factor (LIF) is a polyfunctional cytokine with a variety and a diverse range of biological activities. However, this is a reflection of the fact that the cytokine is expressed in many different tissues, has a wide target cell range, and fulfills different functions in different tissues. The purpose of this article is to examine what is known about LIF expression in the skin and to consider whether LIF plays a role in inflammatory and hyperplastic events in the skin. LIF is strongly expressed in skin tumors, and recent studies indicate that it may affect tumor growth by several different mechanisms. The biological activities of LIF relevant to carcinogenesis, its expression, and signal transduction by the LIF receptor are described. Expression of LIF in normal skin by skin tumors and its induction by ultraviolet radiation and proinflammatory stimuli are discussed, as are possible interactions between LIF, mast cells, and tumor growth. We consider what role LIF and other members of the hemopoietin family of cytokines play in healthy and diseased skin and whether LIF could play a role in hyperplastic skin disorders. LIF appears to be an important cytokine for normal keratinocyte growth and wound healing and may be involved in regulating the proliferation of skin tumors. Accordingly, LIF may be a useful target for anticancer therapy and as a growth factor for normal skin during reconstructive surgery. R. C. MCKENZIE, MBA, PHD, AND J. SZEPIETOWSKI, MD, PHD HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS. [ABSTRACT FROM AUTHOR]

A positive association between intake of calcium channel blockers and psoriasis has been observed recently. Intake of blockers of voltage-gated calcium ion channels is associated with outbreaks of psoriasis after a latent period in patients with and without a previous family history of psoriasis. This suggests that interfering with calcium influx may trigger psoriasis. Calcium influx also occurs via cyclic guanosine monophosphate-gated channels; human keratinocytes contain functional and non-functional (splice variants) versions of these channels. We show here that keratinocytes and skin from psoriatic individuals express higher levels of mRNA encoding a non-functional cyclic guanosine monophosphate-gated calcium channel and that high expression of the splice variant by transfection of cells in culture leads to loss of protein expression for the functional cyclic guanosine monophosphate-gated Ca 2+ channels. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the Hodgkin transformation of small lymphocytic lymphoma in the gastrointestinal tract.

Recent studies published in Oncogene and Proc. Natl. Acad. Sci. USA ascribe a role for selenium, acting through wild type p53, in protecting skin cells in culture from ultraviolet radiation-induced death. While selenium clearly protects cells against ultraviolet radiation-induced death, data that we present and discuss in this letter shows that wild type p53 is not required for such protection. Moreover the non-physiologically high levels of selenium used in some studies leads us to question the relevance of such effects for selenium-induced photoprotection. [Copyright &y& Elsevier]

• This ESMO Clinical Practice Guideline update provides key recommendations for managing acute lymphoblastic leukaemia. • The update covers recent developments in the use of targeted therapies. • Algorithms for the management of newly diagnosed and relapsed or refractory disease are provided. • The author group encompasses a multidisciplinary group of experts from different institutions in Europe. • Recommendations are based on available scientific data and the authors' collective expert opinion. [ABSTRACT FROM AUTHOR]

The mechanisms whereby narrowband ultraviolet B (UVB) (311–313 nm, TL01) phototherapy are effective in psoriasis may differ from those occurring in broadband UVB phototherapy. In the present study, changes in epidermal cells as a result of TL01 therapy were assessed in the skin of patients with psoriasis. The non-lesional skin of five subjects with plaque psoriasis was biopsied before and after a series of 12 whole-body TL01 treatments. Following appropriate staining of skin sections, the numbers of p53-positive keratinocytes, sunburn cells and Langerhans cells in the epidermis were counted. TL01 therapy induced a threefold increase in the number of p53-positive epidermal cells, a 12-fold increase in sunburn cells and a twofold decrease in Langerhans cells. The increase in epidermal p53 expression and apoptosis of keratinocytes together with the depletion of Langerhans cells in the non-lesional skin of psoriasis patients are likely to contribute to the effectiveness of TL01 phototherapy. [ABSTRACT FROM AUTHOR]

Describes the leukemia inhibitory factor (LIF) expression in the skin of patients with amyotrophic lateral sclerosis (ALS). Pattern of LIF staining in normal skin; Use of different antibodies in detecting LIF expression; Effects of LIS on ALS epidermis.

Purpose/objective(s): Radiotherapy (RT) has potential synergistic effects with CD19 CAR-T but is not yet widely used as bridging therapy for lymphoma. Comprehensive outcome data of RT bridged patients are limited, and selection criteria for RT bridging and optimal dose / fractionation are unknown. We hypothesized that RT is a safe, well tolerated and effective bridging to CAR-T even in patients with advanced stage and high-risk features. We analyzed details of RT bridging in a prospective national CAR-T cohort, examining patient, disease and treatment factors which may affect outcome of RT bridging.Materials/methods: We analyzed consecutive patients with r/r high-grade lymphoma who had leukapheresis for axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between Dec 2018 - Nov 2020 in 10 UK centers and received RT bridging.Results: Of 371 leukapheresed patients, 76 (21%) received RT bridging (61 RT alone, 15 combined modality treatment (CMT)). Median age was 58 years. 65% had de novo diffuse large B-cell lymphoma, 7% primary mediastinal B-cell, and 28% transformed lymphoma. 64 were infused (50 axi-cel, 14 tisa-cel), with a median turnaround time of 44 days from apheresis to infusion. 12/75 (16%) patients did not proceed to CAR-T infusion (6 progressive disease (PD), 4 deaths (not related to RT), 1 manufacturing failure, 1 CR after bridging). The dropout rates were 11%, 33% & 22% for RT, CMT and chemotherapy-bridged patients respectively (P = 0.086). Disease characteristics were similar in RT & CMT groups; the majority had advanced stage (71% and 86%), 34% & 43% bulky disease, 59% & 73% extranodal involvement, 55% & 57% were primary refractory to R-CHOP, 75% & 67% had SD/PD as best response to last treatment, 18% & 13% had prior autologous transplant, and 31% & 33% had double/triple hit or -expression. In-field response in 53 cases bridged with RT alone (doses 20 - 40Gy) was 85% (11/14) for early stage (3 CR) and 63% (22/35) for advanced stage. Details of the radiation techniques and RT-related toxicities will be provided at the meeting. The ongoing overall response rate at 3 months post infusion was 63% (50% CR). With a median follow-up of 11.5 months, the median time to progression has not been reached. The 6- & 12-months event-free survival was 60% (95% CI: 47-71) and 58% (95% CI: 45 -69), respectively, with no significant difference between RT and CMT. The median overall survival (OS) was 17.8 months (95% CI: 8.9-NR), with 6- & 12-months OS rates of 77% (95% CI: 64 - 86) and 65% (95% CI: 50-76). Post CAR-T toxicity was favorable, with 7/64 (11%) experiencing G3/4 cytokine release syndrome, 8/64 (13%) G3/4 neurotoxicity. Treatment-related mortality was 4.6%.Conclusion: RT is a safe and effective bridging therapy prior to CD19 CART in lymphoma. In this large prospective real world national cohort with high proportion of advanced stage and high-risk features, RT bridging was given successfully with low dropout rate and excellent survival outcomes. [ABSTRACT FROM AUTHOR]

Summary Herpes simplex virus (HSV) is known to possess several mechanisms whereby it can evade the normal host immune defences. In this study the expression of the immunosuppressive cytokine, interleukin (IL)-10, was monitored following infection of a murine keratinocyte cell line (PAM-212) and compared with the expression of two proinflammatory cytokines: IL-1α and tumour necrosis factor (TNF)-α. The PAM-212 cells were infected at a multiplicity of 0·5 with a clinical isolate of HSV type 1, and the mRNA of the three cytokines was assessed by semiquantitative reverse transcription–polymerase chain reaction (RT–PCR) over the following 24 hr. By 12 hr postinfection the amount of IL-10 mRNA had increased significantly to five-fold greater than that found in uninfected cells (P < 0·01), and this elevated level was maintained until at least 24 hr postinfection. In contrast, IL-1α and TNF-α mRNAs were not significantly up-regulated by the HSV infection. Immunostaining with an IL-10 monoclonal antibody (mAb) revealed that cytoplasmic IL-10 protein had increased by 6–12 hr postinfection. This quantity was further increased at 24 hr postinfection, when the viral cytopathic effect was apparent. Viral replication was necessary, but not sufficient on its own, for IL-10 induction. Experiments with HSV mutants lacking functional transactivating factors suggested that the viral transactivating proteins ICP-0 and VP-16 may be necessary for HSV-induced IL-10 expression. Thus, the up-regulation in the expression of IL-10 mRNA and protein induced by HSV early in the infection of keratinocytes represents a specific response and may be part of the viral strategy to avoid local immune defence mechanisms in the skin. [ABSTRACT FROM AUTHOR]

Selenium (Se) has protective properties against ultraviolet (UV)-induced changes in skin cells in vitro but little is known about such activity in human subjects. In the present study, seven patients with psoriasis ingested 400 μg of sodium selenite daily during a 4 week course of whole-body narrow-band UVB (TL01) therapy while six more psoriasis patients, similarly irradiated, ingested a placebo. Skin biopsies, collected at the start and end of the phototherapy were analysed for phosphorylated p53, Fas, Bcl-2, Bax and oxidized guaninosine, and for numbers of Langerhans and sunburn cells. Following the TL01 therapy, no significant difference was observed for any of these markers when the Se group was compared with the placebo group of patients, although p53 and Bcl-2 expression decreased in the Se supplemented group. [ABSTRACT FROM AUTHOR]